Natural killer cell inhibitory receptor (KIR and NKG2A) (KIR/NKG2A)

The inhibitory interaction between Natural Killer (NK) cell receptors and recipient Human Leukocyte Antigen (HLA) class I molecules is a critical immune checkpoint mechanism that maintains self-tolerance and prevents the destruction of healthy tissues [1][2]. This axis primarily involves two classes of receptors: the Killer-cell Immunoglobulin-like Receptors (KIRs), which recognize classical HLA-A, -B, and -C molecules, and the CD94/NKG2A heterodimer, which recognizes the non-classical HLA-E molecule [3]. Many tumors exploit this system by maintaining or upregulating HLA expression to deliver inhibitory signals to NK cells and certain T cell subsets, effectively evading immune surveillance [1][3]. Therapeutic intervention focuses on using monoclonal antibodies, such as monalizumab (targeting NKG2A) and lirilumab (targeting KIRs), to block these inhibitory signals and 'release the brakes' on the immune system [4][5]. By disrupting this interaction, these drugs enhance the ability of NK cells to identify and lyse tumor cells that would otherwise be protected by HLA expression [1]. This strategy is currently being evaluated in clinical trials, often in combination with other checkpoint inhibitors like PD-1/PD-L1 blockers, to improve therapeutic outcomes in both solid tumors and hematological malignancies [4].

Other names

NK cell inhibitory receptorsHLA class I inhibitory receptorsKiller-cell immunoglobulin-like receptorNKG2ACD94/NKG2AKIR

Blockade of inhibitory signaling pathways (specifically KIR/HLA-C and NKG2A/HLA-E) to restore and enhance the cytotoxic activity of Natural Killer (NK) cells and CD8+ T cells against malignant or infected cells.